A method for preparing 5-deazariboflavins has been described in D. E. O'Brien, L. T. Weinstock and C. C. Cheng, Chem. Ind., 2044 (1967) and J. Heterocycl. Chem., 7. 99 (1970). According to the numbering system adopted by these two references, 5-deazariboflavin is described as "10-deazariboflavin". The process described by O'Brien et al., based on the condensation of anthranilaldehydes with barbituric acid, entails a large number of steps and results in relatively low overall yields and is consequently cumbersome for large scale preparations.
The synthesis of 5-deazariboflavins from 6-(N-alkylanilino)uracils has been described by F. Yoneda and Y. Sakuma, J.C.S. Chem. Comm., 203 (1976). Yoneda et al. obtain 5-deazariboflavin analogs by the treatment of the corresponding 6-(N-alkylanilino)uracils with a mixture of phosphorous oxychloride or ethyl chloroformate and dimethylformamide. The process had not been extended to 5-deazariboflavin itself. F. Yoneda et al., J. Chem. Soc., Perkin Transactions I, 1805 (1976), disclose a process for preparing 5-deazariboflavins by cyclization of the corresponding uracil derivative with triethylorthoformate in dimethylformamide.
M. Janda and P. Hemmerich, Angew. Chem. Int. Ed. Engl., 15, 433 (1976) disclose a process for preparing 5-deazariboflavin via 6-(N-D-ribityl-3,4-xylidino)uracil wherein the ribityl side chain of said uracil derivative is acetylated prior to cyclization with POCl.sub.3 and dimethylformamide. The resulting acetylated 5-deazariboflavin is deacetylated to obtain 5-deazariboflavin.
A method for preparing 6-(N-alkylanilino)uracils is described in F. Yoneda, Y. Sakuma, M. Ichiba, and K. Shinomura, Chem. Pharm. Bull., 20, 1832 (1972); F. Yoneda and Y. Sakuma, Japanese Patent 73 99, 183 (1973); Zh. I. Litvak, S. I. Peretokina, N. I. Kirillova, and V. M. Berezovskii, Zhur, Obshch. Khim., 44, 1401 (1974) and F. Yoneda, Y. Sakuma, M. Ichiba, and K. Shinomura, J. Amer. Chem. Soc., 98, 830 (1976).
Yoneda et al. prepare 6-(N-alkylanilino)uracils by fusing 6-halogenouracils with N-alkylarylamines; sometimes in the presence of a small amount of dimethylformamide. Litvak et al. carry out the same reaction in boiling butanol solution. In some cases, especially with hydroxylated alkyl side chains, these processes have not been reproducible. The reactions do not go to completion and the products are difficult to purify.
The present invention is the process for the synthesis of 5-deazariboflavins (and alkoxymethylene and alkanoyl derivatives thereof) via a ring closure step catalyzed by a strong acid and carried out under anhydrous conditions, designed to be simple, economical and suitable for large-scale preparations. The process is set forth in general terms in Schemes (I) and (II). Scheme (IV) illustrates the process applied specifically to the preparation of 5-deazariboflavin. The key step of the process i.e., the ring closure of the uracil derivatives (III), (VIII) and (XIX) with trialkylorothoformate in the presence of a strong acid catalyst under anhydrous conditions to form 5-deazariboflavins (IV), (IX) and (XX) respectively, is illustrated by the reactions in Scheme (I), Step 2; Scheme (II), Step 3; and Scheme (IV), Step 4 respectively.
Scheme (I) and (II) differ from each other with respect to the groups present at the 8- and 10-position. The Schemes illustrate the blocking and deblocking steps necessary when reactive groups are present at these two positions. Scheme (I) illustrates the case wherein R.sub.10 is a side chain containing hydroxy groups. Reaction of the uracil derivative (III) with a trialkylorthoformate in the presence of a strong acid catalyst selected from the group consisting of strong mineral acids, Lewis acids and organic-based acids such as sulfonic and phosphonic acids under anhydrous conditions yields an alkoxymethylene deazariboflavin (IV) which is readily hydrolyzed to give the deazariboflavin compound. Scheme (II) illustrates the case wherein reactive hydroxy groups at the 8- and 10-positions are acylated (Step 2) prior to cyclization (Step 3). After cyclization, the acyl groups are hydrolyzed (Step 4). Scheme (IV) illustrates the case wherein the specific compound 5-deazariboflavin is prepared.
An improved process for the preparation of the uracil derivatives (III), (VII) and (XIX) is also disclosed. The improvement comprises the use of an excess of the aniline derivatives (II), (VI) and (XVIII) with respect to 6-chlorouracil and the use of water as a solvent. The preferred ratio of aniline derivative to 6-chlorouracil is approximately 3:1. The advantage in using an excess of the aniline derivative is the complete reaction of the 6-chlorouracil. The excess aniline derivative is usually recoverable quantitively at the end of the reaction.
The riboflavin derivatives wherein the side chain at the 10-position is a hydroxylated alkyl chain, such as ribityl, can be converted to the corresponding alkoxymethylene derivative. This process is illustrated by the reverse of Step 5 in Scheme (IV), wherein 5-deazariboflavin (XXI) is converted to the methoxymethylene derivative (XX) by the treatment of (XXI) with trimethylorthoformate in the presence of a sulfonic acid catalyst. ##STR2## R.sub.6 is H or alkyl containing 1 to 3 carbon atoms; R.sub.7 is H or methyl;
R.sub.8 is alkyl containing 1 to 3 carbon atoms or hydroxy; PA1 R.sub.10 is --CH.sub.2 --(CHOH).sub.m --CH.sub.2 Oh
wherein m is 1 or 3; R.sub.11 is ##STR3## wherein R.sub.12 is alkyl containing 1 to 2 carbon atoms and n is 1 or 2. ##STR4## wherein R.sub.6, R.sub.7, R.sub.10 and R.sub.12 are as defined above; R.sub.14 is --CH.sub.2 --(CHOR.sub.15).sub.m --CH.sub.2 OR.sub.15 wherein R.sub.15 is alkanoyl containing 2 to 3 carbon atoms and m is as defined above.
It is to be understood that the present process is equally applicable to the preparation of deazariboflavins having other substituents than those recited above. Illustrations of other suitable groups are set forth in Scheme III. ##STR5## wherein R.sub.6, R.sub.7, R.sub.8 and R.sub.12 are as defined above; R.sub.16 is ##STR6## wherein R.sub.17 is alkyl containing 2 to 4 carbon atoms; R.sub.18 and R.sub.19 are alkyl containing 1 to 2 carbon atoms; or a ring substituted benzyl having the structure: ##STR7## wherein R.sub.20 is alkyl containing 1 to 3 carbon atoms; X is halogen and p is 1 to 3.
If R.sub.8 is hydroxy, it may be preferred to acylate said hydroxy group prior to cyclization as illustrated in Scheme II.
The process for preparing the aniline compounds (II), (VI) and (XVIII) is known to those skilled in the art. The aniline compounds are treated in water with 6-chlorouracil wherein the molar ratio of the aniline compound to 6-chlorouracil is about 3:1. The process of the present invention is directed to cyclizing the resulting uracil derivatives (III), (VIII) and (XIX) by treating said uracil derivatives with excess trialkylorthoformate having the structure HC(OR.sub.12).sub.3 wherein the alkyl group R.sub.12 contains 1 to 2 carbon atoms in the presence of a strong acid catalyst under anhydrous conditions to obtain the 5-deazariboflavin compounds (IV), (IX) and (XX) and when desired hydrolyzing any blocking groups to obtain compounds (V), (X), and (XXI).
Suitable strong acid catalysts useful in carrying out the process of the present invention are strong mineral acids, Lewis acids and organic-based acids such as sulfonic and phosphonic acids. Preferred mineral acids are selected from the group consisting of anhydrous hydrochloric acid, sulfuric acid, anhydrous phosphoric acid and anhydrous phosphorus acid. Preferred Lewis acids are selected from the group consisting of BF.sub.3, ZnCl.sub.2, TiCl.sub.4, SnCl.sub.4 and AlCl.sub.3. Preferred organic-based acids include sulfonic acids selected from aromatic or aliphatic sulfonic acids, such as, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid and ethanesulfonic acid and phosphonic acids such as phenylphosphonic acid.
The excess loweralkoxyorthoformate acts as both reactant and solvent. If needed, a co-solvent may be added to obtain complete solution of the uracil derivative. Suitable co-solvents are dimethylsulfoxide, acetonitrile, diglyme, tetramethylenesulfone, 1,2-dimethoxyethane and dioxane. Dimethylformamide may be employed but not in the case wherein hydroxylated side chains are present if isolation of the alkoxymethylene derivative is desired.
In the case illustrated by Scheme I wherein R.sub.10 in compound (III) is the hydroxylated alkyl group --CH.sub.2 --(CHOH).sub.m --CH.sub.2 OH wherein m is 1 or 3, treatment with a trialkylorthoformate results in the orthoformylation of the hydroxy groups in R.sub.10 to give the alkoxymethylene derivative (IV) wherein R.sub.11 has the structure: ##STR8## wherein R.sub.12 is alkyl containing 1 to 2 carbon atoms and n is 1 to 2. A particular advantage of the present orthoformate cyclization is the in situ protection of the hydroxy groups in R.sub.10 side chain by converting the hydroxy groups to stable, readily isolated alkoxymethylene derivatives which can be hydrolyzed in high yield to the desired 5-deazariboflavin derivative (V) wherein R.sub.10 is --CH.sub.2 --(CHOH).sub.m --CH.sub.2 OH wherein m is 1 or 3. Hydrolysis is readily carried out with dilute mineral acid such as 1N--NCl.
In the case illustrated by Scheme II, the hydroxy groups in compound (VII) are acylated prior to ring closure with trialkylorthoformate. In compound (VII), R.sub.10 is a hydroxylated alkyl group --CH.sub.2 --(CHOH).sub.m --CH.sub.2 OH wherein m is 1 or 3. Treatment with an acylating agent results in the acylation of the hydroxy groups in R.sub.10 to give the corresponding acyloxy derivatives (VIII) wherein R.sub.14 has the structure: EQU --CH.sub.2 --(CHOR.sub.15).sub.m --CH.sub.2 OR.sub.15
wherein R.sub.15 is alkanoyl containing 2 to 3 carbon atoms and m is 1 or 3. Acylation is carried out by using conventional methods, such as an acid anhydride in the presence of an organic base. Preferred acylating agents are acetic or propionic anhydride in the presence of pyridine or zinc chloride.
After cyclization of acylated (VIII) with trialkylorthoformate in the presence of a strong acid catalyst under anhydrous conditions, according to Scheme II, Step 3, the alkanoyl groups R.sub.15 are readily removed by conventional methods, such as treatment with methanolic HCl, dilute aqueous solutions of inorganic base, such as 2.5 N NaOH or aqueous HCl solutions. The preferred method is treatment with concentrated aqueous HCl at room temperature. Removal of the alkanoyl groups provides 5-deazariboflavin derivatives (X) wherein R.sub.10 is --CH.sub.2 --(CHOH).sub.m --CH.sub.2 OH wherein m is 1 or 3.
The alkoxymethylene derivatives of 5-deazariboflavins having the structure: ##STR9## wherein R.sub.6 is H or lower alkyl containing 1 to 3 carbon atoms; R.sub.7 is H or methyl; R.sub.8 is lower alkyl containing 1 to 3 carbon atoms; R.sub.12 is alkyl containing 1 to 2 carbon atoms and n is 1 to 2, can also be prepared by treating the compounds having the structure: ##STR10## wherein R.sub.6, R.sub.7 and R.sub.8 are as defined above and m is 1 or 3 with trialkylorthoformate wherein the alkyl group contains 1 to 2 carbon atoms in the presence of a strong acid catalyst under anhydrous conditions.
The alkoxymethylene derivatives obtained thereby are useful as prodrug forms of 5-deazariboflavin coccidiostats.